There are four million people with Alzheimer's disease (AD) in the U.S. alone and the cost of their care is currently estimated at 100 billion dollars. Available therapy is limited to symptomatic relief without affecting the underlying cause of the disease. Recent evidence indicates that apolipoprotein E (apoE) may play a direct role in neuropathological changes that occur in AD. In particular, apoE has been shown to exhibit neurotoxic activity with isoform specificity that parallels the risk of disease. We have found that the neurotoxic activity of apoe can be blocked by specific compounds, suggesting a novel approach to the design of new therapeutic agents for treatment of Alzheimer's disease. Phase I has been successful. The feasibility of screening novel compounds has been demonstrated. Many of these show efficacy in an in vitro assay designed to mimic the proposed neurotoxic properties associated with apoE. The goals of phase II are to: accelerate in vitro screening, carry out refined analysis of positive compounds, synthesize novel compounds based on positive results, and screen for non-target properties of effective compounds. PROPOSED COMMERCIAL APPLICATION: There are currently no effective treatments for Alzheimer's disease. The identification and development of an agent that significantly delays either the onset or progression of the disease would address a current healthcare cost of several billion dollars.